Cell stem cell, 2013-09, Vol.13 (3), p.351-359
2013
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- Autor(en) / Beteiligte
- Titel
- FGF Signaling Inhibition in ESCs Drives Rapid Genome-wide Demethylation to the Epigenetic Ground State of Pluripotency
- Ist Teil von
- Cell stem cell, 2013-09, Vol.13 (3), p.351-359
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2013
- Quelle
- EZB-FREE-00999 freely available EZB journals
- Beschreibungen/Notizen
- Genome-wide erasure of DNA methylation takes place in primordial germ cells (PGCs) and early embryos and is linked with pluripotency. Inhibition of Erk1/2 and Gsk3β signaling in mouse embryonic stem cells (ESCs) by small-molecule inhibitors (called 2i) has recently been shown to induce hypomethylation. We show by whole-genome bisulphite sequencing that 2i induces rapid and genome-wide demethylation on a scale and pattern similar to that in migratory PGCs and early embryos. Major satellites, intracisternal A particles (IAPs), and imprinted genes remain relatively resistant to erasure. Demethylation involves oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), impaired maintenance of 5mC and 5hmC, and repression of the de novo methyltransferases (Dnmt3a and Dnmt3b) and Dnmt3L. We identify a Prdm14- and Nanog-binding cis-acting regulatory region in Dnmt3b that is highly responsive to signaling. These insights provide a framework for understanding how signaling pathways regulate reprogramming to an epigenetic ground state of pluripotency. •Genome-wide analysis of 2i ESCs reveals demethylated genome similar to ICM and PGCs•Demethylation involves TETs, replicative loss of 5mC and 5hmC, suppression of Dnmt3s•NANOG/PRDM14 binding element in Dnmt3b enhancer is highly responsive to signaling•2i and serum epigenetic signatures exist in populations of NanogGFP ESCs and ICM The transition to ground state pluripotency involves genome-wide DNA demethylation and oxidation of 5mC to 5hmC by Tet proteins.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1934-5909, 1875-9777eISSN: 1875-9777DOI: 10.1016/j.stem.2013.06.004Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3765959
- Format
- –
- Schlagworte
- Animals, Cell Line, DNA (Cytosine-5-)-Methyltransferases - genetics, DNA (Cytosine-5-)-Methyltransferases - metabolism, DNA Methylation - drug effects, DNA Methyltransferase 3B, DNA-Binding Proteins - genetics, DNA-Binding Proteins - metabolism, Embryonic Stem Cells - drug effects, Embryonic Stem Cells - physiology, Epigenetic Repression, Epigenomics, Fibroblast Growth Factors - metabolism, Genome - genetics, Germ Cells - physiology, Homeodomain Proteins - genetics, Homeodomain Proteins - metabolism, MAP Kinase Signaling System - drug effects, Mice, Nanog Homeobox Protein, Pluripotent Stem Cells - drug effects, Pluripotent Stem Cells - physiology, Protein Binding, Protein Kinase Inhibitors - pharmacology, Proto-Oncogene Proteins - genetics, Proto-Oncogene Proteins - metabolism, Regulatory Sequences, Nucleic Acid - genetics, RNA-Binding Proteins, Short, Transcription Factors - genetics, Transcription Factors - metabolism